In the conventional pharmaceutical preparations for oral administration which contains a slightly soluble medicament, the medicament shows a small dissolution rate in the digestive tract. Therefore, the amount of the dissolved medicament per a certain time of period is small, the absorption of the medicament through the digestive tract is delayed, and the amount of the medicament absorbed through the digestive tract per hour becomes small, resulting in slow absorption in a living body and a low bioavailability. In these situations, improvement in solubility of the slightly soluble medicament has been desired for effective manifestation of the efficacy and the quick-acting nature of the medicament.
As examples of the methods previously proposed for improving the solubility of a slightly soluble medicament, Japanese Patent No. 2516524 discloses a method for reducing the particle size of and amorphizing a slightly soluble, crystalline medicament (e.g., nifedipine, indomethacin); and Japanese Patent Application Laid-open Publication No. 54-2316 discloses a method for preparing powders or granules from solid dispersions comprising nifedipine and polyvinylpyrrolidone, which comprises dissolving nifedipine and polyvinylpyrrolidone in an organic solvent (e.g., methanol) to give a solution and then removing the organic solvent therefrom.
Among the commercially available nifedipine preparations, a preparation in which poly(ethylene glycol) is used to form a solid dispersion of nifedipine is "Adalat" (Bayer); and a preparation in which nifedipine is dissolved in an organic solvent and coated on lactose is "Sepamit" (Kanebo, Ltd.).
As a example of amorphization, Japanese Patent Publication No. 54-29565 discloses a method comprising adding a plurality of medicaments including a slightly soluble base medicament into a .beta.-1,4-glucane and co-ground the medicaments. In this method, the .beta.-1,4-glucane used is a microcrystalline cellulose "Avicel" (a trade name, Asahi Chemical Industry Co., Ltd.); examples of the slightly soluble base medicament are phenacetin, phenoxymethyl penicillin and phenobarbital; examples of the other medicaments simultaneously used with the base medicament are slightly soluble cortisone acetate, soluble tetracycline hydrochloride and water-soluble pyridoxine hydrochloride; the grinding apparatus for co-grinding of the medicaments is one having mechanisms for mechanically crushing and grinding the medicaments into a microcrystalline form, such as a ball mill; and the co-grinding is continued until the crystalline substances cause no diffraction peak specific to the crystalline substances, that is, from several hours to 10-odd hours which is required for complete amorphization.
Methods for preparing a solid dispersion of nifedipine with an organic solvent are disclosed in Japanese Patent Application Laid-open No. 54-2316 (supra) and Japanese Patent Publication No. 3-7645.
A method for improving the dissolution rate of a slightly soluble medicament is disclosed in Japanese Patent Publication No. 5-66364 in which a slightly soluble medicament and a water-soluble polymer are fed to a twin-roll mill (which is equipped with horizontal two rolls which rotate in opposing directions to each other) through a gap between the rolls while rotating the rolls, and kneaded by the rotation of the rolls.
A method for preparing an easy-absorbable nifedipine preparation which is stable to moisture is disclosed in Japanese Patent Publication No. 3-28404, by which it becomes possible to improve the dissolution properties, particular dissolution rate, of nifedipine in water and, thereby, to produce a preparation stable to moisture compared to the conventional solid solution powdery preparations containing polyvinylpyrrolidone.
This method comprises the steps of granulating a pharmaceutical additive (e.g., lactose) and a water-soluble binder (e.g., polyvinylpyrrolidone) to give a water-soluble fine particulate carrier, spraying a solution of nifedipine and either hydroxypropylmethylcellulose or methylcellulose in a solvent (e.g., ethanol) on the carrier, and then drying the sprayed carrier. The nifedipine preparation provided by this method is one in which nifedipine is coated in the form of a solid dispersion. The preparation thus produced is easy-to-dissolve or easy-to-absorb and is stable to moisture.
A medicament complex comprising a base medicament hardly soluble to water (e.g., phenacetin) which is carried on the surface of a modified starch (e.g., pregelatinized starch), is disclosed in Japanese Patent Publication No. 7-47548. In this patent publication, it is described that the dissolution rate of the base medicament of the medicinal complex is increased as determined by the dissolution test (the second solution, pH 6.8) of the base medicament performed in accordance with the paddle method described in the Japanese Pharmacopoeia Tenth Edition, and thereby the solubility of the base medicament is improved.
A method for improving the dissolution properties of a crystalline medicament that is intestinally slightly soluble to the intestinal juice is disclosed in Japanese Patent Application Laid-open No. 6-227969. This method comprises the steps of dissolving an enteric polymer (e.g., calboxymethylethylcellulose; a product of FREUND INDUSTRIAL CO., LTD.) with a mixed solvent of methylene chloride and ethanol to give a solution, dispersing indomethacin particles (mean particle diameter: 10 .mu.m) or mefenamic acid particles (mean particle diameter: 27 .mu.m) in air as the crystalline medicament particles slightly soluble to the intestinal juice, spraying the above-prepared solution to the particles to adhere the enteric polymer on the particles, and drying the particles.
A method for improving the dissolution properties of a crystalline medicament slightly soluble to water is disclosed in Japanese Patent Application Laid-open No. 7-112928. This method comprises the steps of dissolving nifedipine (mean particle diameter: 20 .mu.m) into ethanol to give a solution, spraying the solution to a hydrophilic substance (e.g., lactose; mean particle diameter: 5-10 .mu.m) to make carry the medicament (i.e., nifedipine) on the hydrophilic substance, granulating the medicament-carried hydrophilic substance together with a water-soluble polymer (e.g., hydroxypropyl cellulose) as a binder.
Alginate gel beads are disclosed in Japanese Patent Application Laid-open No. 2-167220, where a sustained-release preparation is described in which a basic medicament (e.g., nifedipine) is included in the alginate gel beads. In this patent application, the sustained-release preparation is produced by adding a suspension of the basic medicament in a sodium alginate solution to a calcium chloride solution dropwise through a nozzle, keeping the solution to stand, thereby forming alginate gel beads as the sustained-release preparation. In this case, the obtained alginate gel beads are assumed to be converted to calcium alginate gel beads.
Japanese Patent Application Laid-open No. 5-39228 discloses calcium alginate beads containing nifedipine, which is prepared by adding an alginic acid propylene glycol ester and/or sodium alginate to water to give a solution, adding the solution to a calcium chloride solution dropwise through a nozzle, stirring the solution, keeping the resultant solution to stand for 72 hours, washing the solution with water, drying the solution in air, and then further drying the resultant in vacuo at room temperature. The beads thus prepared act as a sustained-release preparation, and is assumed to take a gel form.
Japanese Patent Application Laid-open No. 5-222208 discloses perfectly spherical calcium alginate beads in which alginic acid is ion-crosslinked via bivalent metal ions such as calcium ions and which have a particle size ranging from 0.1 to 30 .mu.m.
Japanese Patent Application Laid-open No. 6-100468 discloses a sustained-release composition comprising a content to be released (e.g., phenytoin, diclofenac sodium, brilliant blue), alginic acid and hyaluronic acid. In this patent application, a typical sustained-release preparation is prepared by adding an aqueous solution containing diclofenac sodium, sodium alginate and hyaluronic acid to a calcium chloride solution dropwise through a nozzle, keeping the solution to stand at room temperature for 24 hours, and washing the solution with distilled water. In this method, it is thought that the sodium alginate used is converted into gelatinous calcium alginate.
Japanese Patent No. 2516524 discloses a method in which nifedipine or indomethacin and crosslinked polyvinylpyrrolidone are ground while mixing continuously for 48 hours with a ball mill to amorphize the nifedipine or indomethacin. This method has such a disadvantage that it requires too much time to grind. Japanese Patent Publication No. 54-29565 discloses a method in which microcrystalline cellulose and a medicament are co-ground until any diffraction peak caused by the crystal structure disappear. This method also has a disadvantage that it requires too much time to co-grind. Therefore, both the methods have a problem in production efficiency.
The method disclosed in Japanese Patent Application Laid-open No. 54-2316 is a wet system with an organic solvent. In the composition produced by this process, nifedipine is present in the state where nifedipine is dissolved in a matrix (e.g., polyvinylpyrrolidone) to form a glassy or solid solution-like structure. Accordingly, the composition is not well satisfactory from the veiwpoint of rapid dissolution of nifedipine in the intestine.
The method disclosed in Japanese Patent Publication No. 5-66364 has a shorter manufacturing period. However, this method requires a heating process. In the method disclosed in Japanese Patent Publication No. 3-28404, the production process is complicated. Accordingly, both of these methods have a problem of increased production cost. In Japanese Patent Publication No. 7-47548, partially pregelatinized starch is exemplified as a preferable carrier. However, the preparation of this patent publication is not also satisfactory as a controlled-release preparation for releasing the medicament in the intestine, because it carries the medicament only on the surface of the starch.
Each of Japanese Patent Application Laid-open Nos. 2-167220, 5-39228, 6-100468 and 6-25013 discloses a controlled-release preparation in which a medicament is included in calcium alginate gel beads.
Japanese Patent Application Laid-open Nos. 6-227969 and 7-112928 disclose processes performed in air. The processes are not suitable for mass production.
Accordingly, the object of the present invention is to provide a controlled-release preparation capable of rapidly releasing a slightly soluble medicament that has a slow intestinal dissolution rate in the intestine and a process for preparing the controlled-release preparation. Another object of the present invention is to provide a controlled-release preparation capable of releasing in the intestine 99% or more of the slightly soluble medicament from the carrier and a process for preparing the controlled-release preparation.